Extracellular vesicles in AD-like pathology in HIV and its potential therapeutics

HIV 中 AD 样病理学中的细胞外囊泡及其潜在治疗方法

• 批准号: 10618024
• 负责人: Tauheed Ishrat
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618024
• 关键词: Acceleration; Affect; Age; Aging; Alzheimer associated neurodegeneration; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-42; Animals; Anti-Retroviral Agents; Award; Biological Response Modifier Therapy; Blood - brain barrier anatomy; Brain; Bypass; Cells; Central Nervous System Diseases; Cessation of life; Cognitive; Curcumin; Data; Development; Drug toxicity; Early Onset Alzheimer Disease; Enzymes; Formulation; Goals; HIV; HIV Infections; HIV Seronegativity; Human; In Vitro; Induced pluripotent stem cell derived neurons; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Intranasal Administration; Life Expectancy; Macrophage; Measures; Mediating; Memory; Memory impairment; Microglia; Microtubule-Associated Proteins; Modeling; Mus; Nerve Degeneration; Neurocognition; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Penetration; Permeability; Persons; Pharmaceutical Preparations; Population; Premature aging syndrome; Principal Investigator; Proteins; Regimen; Reporting; Research; Research Personnel; Role; Route; Senile Plaques; Site; Symptoms; Synaptophysin; System; TXNIP gene; Testing; Therapeutic; Time; Toxic effect; Transgenic Organisms; Viral Proteins; Virus; aged; antioxidant enzyme; antiretroviral therapy; attenuation; blood-brain barrier crossing; brain cell; brain tissue; cytokine; efficacy evaluation; experience; extracellular vesicles; hyperphosphorylated tau; improved; in vitro Model; inhibitor; mouse model; nanocarrier; nanoformulation; neuroinflammation; neuron loss; novel; protein biomarkers; water maze

Studies of brain tissues from people living with HIV (PLWH) age from 38-60 years, showed increased amyloid plaques and tau hyperphosphorylation compared to age-matched HIV-negative subjects. PLWH who are on antiretroviral therapy (ART) live longer but experience neurodegenerative conditions related to HIV as they age. In 2018, 51% of PLWH in the U.S. were age 50 or older, and in the next 5-10 years, this population will be in their sixties, the prime age when Alzheimer’s disease (AD) symptoms begin to manifest. Further, premature aging with HIV infection is reported to affect neurocognition in PLWH. Since aging is a significant risk factor for AD development and HIV can cause premature aging, it's critically important to examine the relationship between HIV-induced aging and AD. Compared to age-matched HIV-negative subjects, studies of brain tissues from people living with HIV (PLWH) aged 38-60 showed increased amyloid plaques and tau hyperphosphorylation. However, the underlying mechanism by which HIV causes AD-associated neurodegeneration and memory impairment in PLWH is not well studied. Moreover, due to the inability of ARVs to cross the blood-brain barrier (BBB), the current ARV regimens are insufficient in suppressing HIV in the brain, which can further exacerbate neurodegenerative conditions in the aged HIV population. Our preliminary studies have shown that extracellular vesicles (EVs) derived from HIV-infected macrophages carry higher pro-inflammatory cytokines and low antioxidant enzymes. Further, exposure of these EVs from HIV-infected macrophages to SH-SY5Y neuronal cells caused increased toxicity, IL-1β levels, and neuronal loss (MAP2). We have also demonstrated that EVs administered by the intranasal route can bypass the BBB and be detected in the brain. Further, we showed that the elvitegravir (an antiretroviral drug) could be loaded into EVs and delivered across the BBB in an in vitro model. This proposal will elucidate the role of the HIV components packaged in EVs in causing AD-like pathology through the TXNIP inflammatory pathway. We will also use EVs as nanocarriers to improve curcumin (TXNIP inhibitor) and EVG levels across the BBB, thus effectively suppressing inflammation with minimal/tolerable drug toxicity.

研究艾滋病毒（PLWH）年龄从38-60岁患者的脑组织的研究显示 与年龄匹配的HIV阴性受试者相比，淀粉样蛋白斑块和TAU高磷酸化。 plwh谁 正在接受抗逆转录病毒疗法（ART）寿命更长，但经历与HIV有关的神经退行性疾病 他们年龄。 2018年，美国有51％的PLWH年龄在50岁以上，在接下来的5-10岁时，该人口 将在60年代，这是当时阿尔茨海默氏病（AD）症状开始显现的黄金时代。此外， 据报道，HIV感染过早衰老会影响PLWH中的神经认知。由于衰老是一个重大风险 广告发育和艾滋病毒的因素可能导致过早衰老，检查这种关系至关重要 在HIV引起的衰老和AD之间。 与年龄匹配的HIV阴性受试者相比，对HIV患者的脑组织研究 （PLWH）年龄38-60显示淀粉样蛋白斑块和Tau高磷酸化增加。但是，基础 艾滋病毒引起与PLWH中引起广告相关的神经退行性和记忆障碍的机制不是 井研究。此外，由于ARV无法越过血脑屏障（BBB），电流ARV 方案不足以抑制大脑中的HIV，这会进一步加剧神经退行性 老年艾滋病毒人群的状况。我们的初步研究表明，细胞外蔬菜（EV） 源自HIV感染的巨噬细胞具有较高的促炎细胞因子和低抗氧化剂酶。 此外，这些电动汽车从HIV感染的巨噬细胞暴露于SH-SY5Y神经元细胞增加 毒性，IL-1β水平和神经元丧失（MAP2）。我们还证明了由 鼻内路线可以绕过BBB并在大脑中检测到。 此外，我们证明了Elvitegravir（一种抗逆转录病毒药物）可以加载到EV中并递送 在体外模型中跨越BBB。该建议将阐明包装在 通过TXNIP炎症途径引起广告样病理的电动汽车。我们还将使用电动汽车作为 纳米载体改善姜黄素（TXNIP抑制剂）和EVG水平，从而有效抑制 具有最小/可忍受的药物毒性的炎症。